Systemic Lupus Erythematosus Arthritis
Conditions
Keywords
Systemic Lupus Erythematosus (SLE), Abatacept (Orencia), Arthritis
Brief summary
This research trial is for patients who have been diagnosed with systemic lupus erythematosus (SLE) with swollen, tender joints (which is called inflammatory polyarthritis) because of the SLE. The purpose of this clinical research study is to evaluate the safety and effectiveness of treatment with abatacept (Abatacept) 125mg injected subcutaneously (under the skin) weekly for 16 weeks versus placebo injections(a substance with no active ingredients and therefore may have no treatment benefit) in subjects with SLE and inflammatory polyarthritis. The effectiveness will be assessed primarily by the number of swollen, tender joints (called a joint count) at each of study visits. Study Medication Abatacept is approved in the U.S. for treating rheumatoid arthritis by prescription and has not been approved by the U.S. Food and Drug Administration for treating SLE yet. In this study, subjects will receive treatment with either abatacept or placebo once a week for 16 weeks (a total of 16 injections).
Interventions
BIOLOGICALabatacept also known as Orencia also known as CTLA4-Ig
125mg injected subcutaneously weekly for 16 weeks
DRUGPlacebo
Sponsors
Bristol-Myers Squibb
University of California, Los Angeles
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Meet at least 4 of the 11 American College of Rheumatology (ACR) 1997 criteria for classification of SLE (see Appendix 1).OR meet the recent classification recommended by SLICC (Appendix 2) 6 2. ≥3 swollen and tender joints on 2 examinations at least 2 weeks apart and no more than 8 weeks apart. 3. SLEDAI2K score ≥4 indicating active disease. 4. Documented positive ANA (≥1:80) and/or anti-dsDNA during course of SLE. 5. Men and women, at least 18 years of age. Women of childbearing potential must use adequate method(s) of contraception to avoid pregnancy throughout the study and for up to 2 months after last study drug dose. They must have a negative serum or urine pregnancy test prior to the start of study medication. 6. Background therapies allowed: antimalarials (dose constant for ≥ one month before study entry and during 16 weeks of trial), methotrexate (same criteria as for antimalarials), azathioprine (same criteria), mycophenolate (same criteria), leflunomide (same criteria). During the screening period and for up to 6 weeks after randomization, a daily prednisone (or equivalent) regimen of up to 20 mg daily may be initiated to treat the moderate to severe disease activity present at screening. The initial steroid regimen is not required if investigators or patients believe that the risks would outweigh the potential benefits. Patients who do not take any glucocorticoids during the study will be included in the treatment groups and analysis. \*Steroids should be tapered to a target dose of no more than 10 mg/day of prednisone (or equivalent) by the end of Week 8 (Day 56). The steroid regimen should be tapered as quickly as safely possible. Prednisone dose requirements higher than 10 mg daily at the 8 week visit will cause the patient to be ruled a non-responder for the abatacept treatment arm.
Exclusion criteria
1. Subjects with active infection requiring oral or IV antibiotics within one month of first dose of study medication. 2. Subjects with BILAG A in any system outside the musculoskeletal system. 3. Subjects with positive quantiferon Gold test in the absence of treatment for tuberculosis. 4. Subjects with positive tests for active infection with hepatitis B or C during the past 6 months. Any confirmed positive test for HIV at any time prior to entry into this study. 5. Subjects with active glomerulonephritis (\>3 g protein/24h and/or active urine sediment). 6. Subjects with active CNS disease. 7. Subjects with any other serious disease that would require immunosuppressive or parenteral anti-microbial therapy outside the study protocol. 8. Inability to self-administer subcutaneous injections, to comply with instructions, or to keep appointments for study visits. 9. Treatment with rituximab within the past 6 months (B cells must be detectable in peripheral blood at onset of treatment with study biologic), belimumab within the past 5 months, cyclophosphamide within the past 3 months. 10. Treatment with any other immunomodulatory biologic or cyclophosphamide during treatment with abatacept is not allowed. 11. Patients requiring \>20 mg of prednisone daily. 12. Women who are pregnant or breast feeding. 13. Women of child bearing potential unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 2 months after last study drug. 14. Subjects with a history of cancer within the last five years (other than non-melanoma skin cell cancers cured by local resection). 15. Any laboratory test results that, in the opinion of the Investigator, might place the subject at unacceptable risk for participation in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With at Least a 20% Improvement From Baseline in Tender and Swollen 28 Joint Count | Baseline, 8 Weeks, 16 Weeks | Assessed by physical exam. Total number of joints that are both swollen and tender were assessed in each participant by a physician at each study visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the PGA Score | Baseline, 16 weeks | Physician's Global Assessment (PGA) is a physician rating of patient's disease activity, with a range 0-3. A change of 0.8 points on a 3 point scale or less is considered as stable. Lower score means better outcome |
| Clinical Disease Activity Index (CDAI) Index Score | 16 weeks | CDAI is a simplified index for assessing disease activity comprising swollen joint counts (SJC), tender/painful joint counts (TJC), participant's global assessment of disease activity (PtGA) and physician's global assessment of disease activity (PGA). CDAI is the numerical sum of 4 outcome parameters: SJC and TJC (based on 28-joint assessment), PtGA and PGA (assessed on 0-10 cm visual analog scale; higher scores indicated greater affection due to disease activity). CDAI total score = 0-76. CDAI less than equal to (\<=) 2.8 indicates disease remission, greater than (\>) 2.8 to 10 = low disease activity, greater than (\>) 10 to 22 = moderate disease activity, and \>22 = high disease activity. |
| Synovitis, Tenosynovitis and Erosions Scores (GSUS and PDUS) | Baseline, 16 weeks | Using ultrasound analysis, (Gray scale ultrasound) represents synovitis/tenosynovitis and identifies erosions. PDUS (power Doppler ultrasound) measures intensity of soft tissue inflammation by blood flow. 30 joints were evaluated using a 0 to 3 point scale for each joint and the sum of these represents PDUS. The Power Doppler Synovitis Score (PDUS) ranges from 0 to 90. Scores of 0 indicate the least amount of inflammation. A higher value of the total score for PDUS represents more severe disease level. 30 joints were evaluated using a 0 to 3 point scale for each joint and the sum of these represents GSUS. The grey scale synovial hypertrophy score (GSUS) ranges from 0 to 90. Scores of 0 indicate the least amount of inflammation of the joint. A higher value of the total score for GSUS represents more severe disease level. |
| Number of AEs and SAEs | 16 weeks | Total number of AEs and total number of SAEs as well as those AEs/SAEs which may be related to the study drug |
| Change in SLEDAI 2K | Baseline, 16 weeks | Systemic Lupus Erythematosus Disease Activity Index (Modified in the year 2000) - The SLEDAI-2K is a modified version of a composite score based on the presence or absence of clinical signs, clinical symptoms, and immunologic laboratory results taken within 10 days of the evaluations. Each of the descriptors has a weighted score and the total score of SLEDAI-2K is the sum of all 24 descriptor scores. The total SLEDAI-2K score falls between 0 and 105, with higher scores representing higher disease activity. Decrease of 3 points in SLEDAI 2K is considered to be a clinically significant improvement. |
| Change in the Total Sum of Tender and Swollen Joints | Baseline, 16 weeks | Total number of joints that are both swollen and tender were assessed in each participant by a physician at each study visit |
| Number of Patients Who Tapered Prednisone to <10mg/Day | 16 weeks | This analysis is for the subset of patients who start the study taking 10 to 20mg of prednisone per day. |
| Mean Prednisone Dose (mg/Day) | Baseline, 8 and 16 weeks | prednisone dose (mg/day) is recorded at baseline, 8 and 16 weeks for each subject being assessed at that study visit. Then a mean for all the subjects in each group at each time point was calculated. |
| Number of Tender and Swollen Joints | baseline, 4, 8, 12 and 16 weeks | Total number of joints that are both swollen and tender were assessed in each participant by a physician at each study visit |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Abatacept abatacept: 125mg injected subcutaneously weekly for 16 weeks | 15 |
| Placebo Placebo subcutaneous injection weekly for 16 weeks | 13 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | Abatacept |
|---|---|---|---|
| Age, Continuous | 40.8 years STANDARD_DEVIATION 15.3 | 42.2 years STANDARD_DEVIATION 12 | 43.6 years STANDARD_DEVIATION 9 |
| education 2 year college | 6 Participants | 8 Participants | 2 Participants |
| education 4 year college | 1 Participants | 5 Participants | 4 Participants |
| education high school | 1 Participants | 2 Participants | 1 Participants |
| education master's degree | 4 Participants | 6 Participants | 2 Participants |
| education other | 0 Participants | 3 Participants | 3 Participants |
| education professional | 1 Participants | 3 Participants | 2 Participants |
| education trade school | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 9 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 19 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| insurance HMO | 3 Participants | 8 Participants | 5 Participants |
| insurance Medicaid | 2 Participants | 5 Participants | 3 Participants |
| insurance Medicare | 1 Participants | 1 Participants | 0 Participants |
| insurance PPO | 7 Participants | 13 Participants | 6 Participants |
| insurance unknown | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United States | 13 participants | 28 participants | 15 participants |
| Sex: Female, Male Female | 13 Participants | 27 Participants | 14 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 1 Participants |
| smoking history current smoker | 1 Participants | 3 Participants | 2 Participants |
| smoking history never smoked | 9 Participants | 21 Participants | 12 Participants |
| smoking history past smoker | 3 Participants | 4 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 13 |
| other Total, other adverse events | 6 / 15 | 3 / 13 |
| serious Total, serious adverse events | 1 / 15 | 0 / 13 |
Outcome results
Primary
Number of Participants With at Least a 20% Improvement From Baseline in Tender and Swollen 28 Joint Count
Assessed by physical exam. Total number of joints that are both swollen and tender were assessed in each participant by a physician at each study visit.
Time frame: Baseline, 8 Weeks, 16 Weeks
Population: subjects that completed the 8 and 16 week study visits
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Abatacept | Number of Participants With at Least a 20% Improvement From Baseline in Tender and Swollen 28 Joint Count | 8 Weeks | 11 Participants |
| Abatacept | Number of Participants With at Least a 20% Improvement From Baseline in Tender and Swollen 28 Joint Count | 16 Weeks | 10 Participants |
| Placebo | Number of Participants With at Least a 20% Improvement From Baseline in Tender and Swollen 28 Joint Count | 8 Weeks | 11 Participants |
| Placebo | Number of Participants With at Least a 20% Improvement From Baseline in Tender and Swollen 28 Joint Count | 16 Weeks | 10 Participants |
Secondary
Change in SLEDAI 2K
Systemic Lupus Erythematosus Disease Activity Index (Modified in the year 2000) - The SLEDAI-2K is a modified version of a composite score based on the presence or absence of clinical signs, clinical symptoms, and immunologic laboratory results taken within 10 days of the evaluations. Each of the descriptors has a weighted score and the total score of SLEDAI-2K is the sum of all 24 descriptor scores. The total SLEDAI-2K score falls between 0 and 105, with higher scores representing higher disease activity. Decrease of 3 points in SLEDAI 2K is considered to be a clinically significant improvement.
Time frame: Baseline, 16 weeks
Population: completers at 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Abatacept | Change in SLEDAI 2K | -1.4545 score on a scale | Standard Deviation 3.2669 |
| Placebo | Change in SLEDAI 2K | -3.4000 score on a scale | Standard Deviation 2.8363 |
Secondary
Change in the PGA Score
Physician's Global Assessment (PGA) is a physician rating of patient's disease activity, with a range 0-3. A change of 0.8 points on a 3 point scale or less is considered as stable. Lower score means better outcome
Time frame: Baseline, 16 weeks
Population: SLE subjects completing 16 weeks of treatment or placebo and attending the 16-week physician assessment visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Abatacept | Change in the PGA Score | -1.3650 points on scale | Standard Deviation 3.7029 |
| Placebo | Change in the PGA Score | -0.3350 points on scale | Standard Deviation 2.2289 |
Secondary
Change in the Total Sum of Tender and Swollen Joints
Total number of joints that are both swollen and tender were assessed in each participant by a physician at each study visit
Time frame: Baseline, 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Abatacept | Change in the Total Sum of Tender and Swollen Joints | -5.1818 Joints | Standard Deviation 4.2619 |
| Placebo | Change in the Total Sum of Tender and Swollen Joints | -4.2000 Joints | Standard Deviation 1.3116 |
Secondary
Clinical Disease Activity Index (CDAI) Index Score
CDAI is a simplified index for assessing disease activity comprising swollen joint counts (SJC), tender/painful joint counts (TJC), participant's global assessment of disease activity (PtGA) and physician's global assessment of disease activity (PGA). CDAI is the numerical sum of 4 outcome parameters: SJC and TJC (based on 28-joint assessment), PtGA and PGA (assessed on 0-10 cm visual analog scale; higher scores indicated greater affection due to disease activity). CDAI total score = 0-76. CDAI less than equal to (\<=) 2.8 indicates disease remission, greater than (\>) 2.8 to 10 = low disease activity, greater than (\>) 10 to 22 = moderate disease activity, and \>22 = high disease activity.
Time frame: 16 weeks
Population: sle subjects that completed 16 week assessment visit
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Abatacept | Clinical Disease Activity Index (CDAI) Index Score | 14.7850 score on a scale | Standard Deviation 12.0459 |
| Placebo | Clinical Disease Activity Index (CDAI) Index Score | 14.5700 score on a scale | Standard Deviation 7.9701 |
Secondary
Mean Prednisone Dose (mg/Day)
prednisone dose (mg/day) is recorded at baseline, 8 and 16 weeks for each subject being assessed at that study visit. Then a mean for all the subjects in each group at each time point was calculated.
Time frame: Baseline, 8 and 16 weeks
Population: Results are reported for the number of participants who completed the study visit/assessment at each time point
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Abatacept | Mean Prednisone Dose (mg/Day) | 16 weeks | 8.45 mg per day | Standard Deviation 10.04 |
| Abatacept | Mean Prednisone Dose (mg/Day) | baseline | 4.73 mg per day | Standard Deviation 7.73 |
| Abatacept | Mean Prednisone Dose (mg/Day) | 8 weeks | 5.46 mg per day | Standard Deviation 7.98 |
| Placebo | Mean Prednisone Dose (mg/Day) | 16 weeks | 5.70 mg per day | Standard Deviation 7.99 |
| Placebo | Mean Prednisone Dose (mg/Day) | baseline | 4.77 mg per day | Standard Deviation 6.64 |
| Placebo | Mean Prednisone Dose (mg/Day) | 8 weeks | 5.64 mg per day | Standard Deviation 6.89 |
Secondary
Number of AEs and SAEs
Total number of AEs and total number of SAEs as well as those AEs/SAEs which may be related to the study drug
Time frame: 16 weeks
Population: All subjects dosed with either abatacept or placebo at least once.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Abatacept | Number of AEs and SAEs | AEs grade II or less | 20 adverse events |
| Abatacept | Number of AEs and SAEs | AEs not related | 14 adverse events |
| Abatacept | Number of AEs and SAEs | AEs possibly related | 5 adverse events |
| Abatacept | Number of AEs and SAEs | AEs probably related | 1 adverse events |
| Abatacept | Number of AEs and SAEs | AEs grade III or higher | 1 adverse events |
| Abatacept | Number of AEs and SAEs | SAEs | 1 adverse events |
| Placebo | Number of AEs and SAEs | AEs grade III or higher | 0 adverse events |
| Placebo | Number of AEs and SAEs | AEs grade II or less | 27 adverse events |
| Placebo | Number of AEs and SAEs | AEs probably related | 3 adverse events |
| Placebo | Number of AEs and SAEs | AEs not related | 14 adverse events |
| Placebo | Number of AEs and SAEs | SAEs | 0 adverse events |
| Placebo | Number of AEs and SAEs | AEs possibly related | 10 adverse events |
Secondary
Number of Patients Who Tapered Prednisone to <10mg/Day
This analysis is for the subset of patients who start the study taking 10 to 20mg of prednisone per day.
Time frame: 16 weeks
Population: This analysis is for the subset of patients who start the study taking 10 to 20mg of prednisone per day. Among all the subjects entered, 6 in each group were taking 10 mg of prednisone daily or higher at baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Abatacept | Number of Patients Who Tapered Prednisone to <10mg/Day | 2 participants |
| Placebo | Number of Patients Who Tapered Prednisone to <10mg/Day | 0 participants |
Secondary
Number of Tender and Swollen Joints
Total number of joints that are both swollen and tender were assessed in each participant by a physician at each study visit
Time frame: baseline, 4, 8, 12 and 16 weeks
Population: Each timepoint reports the number of participants who attended each visit for physician assessment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Abatacept | Number of Tender and Swollen Joints | week 4 | 2.80 joints | Standard Deviation 2.65 |
| Abatacept | Number of Tender and Swollen Joints | week 12 | 1.58 joints | Standard Deviation 2.19 |
| Abatacept | Number of Tender and Swollen Joints | week 8 | 1.77 joints | Standard Deviation 2.13 |
| Abatacept | Number of Tender and Swollen Joints | week 16 | 1.82 joints | Standard Deviation 2.27 |
| Abatacept | Number of Tender and Swollen Joints | baseline | 6.73 joints | Standard Deviation 4.53 |
| Placebo | Number of Tender and Swollen Joints | week 16 | 0.50 joints | Standard Deviation 0.97 |
| Placebo | Number of Tender and Swollen Joints | baseline | 5.00 joints | Standard Deviation 1.41 |
| Placebo | Number of Tender and Swollen Joints | week 4 | 1.54 joints | Standard Deviation 1.1 |
| Placebo | Number of Tender and Swollen Joints | week 8 | 0.45 joints | Standard Deviation 0.69 |
| Placebo | Number of Tender and Swollen Joints | week 12 | 1.00 joints | Standard Deviation 1.34 |
Secondary
Synovitis, Tenosynovitis and Erosions Scores (GSUS and PDUS)
Using ultrasound analysis, (Gray scale ultrasound) represents synovitis/tenosynovitis and identifies erosions. PDUS (power Doppler ultrasound) measures intensity of soft tissue inflammation by blood flow. 30 joints were evaluated using a 0 to 3 point scale for each joint and the sum of these represents PDUS. The Power Doppler Synovitis Score (PDUS) ranges from 0 to 90. Scores of 0 indicate the least amount of inflammation. A higher value of the total score for PDUS represents more severe disease level. 30 joints were evaluated using a 0 to 3 point scale for each joint and the sum of these represents GSUS. The grey scale synovial hypertrophy score (GSUS) ranges from 0 to 90. Scores of 0 indicate the least amount of inflammation of the joint. A higher value of the total score for GSUS represents more severe disease level.
Time frame: Baseline, 16 weeks
Population: completers of 16 weeks of treatment/placebo at one study center (UCLA)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Abatacept | Synovitis, Tenosynovitis and Erosions Scores (GSUS and PDUS) | baseline GSUS | 17.50 score on scale | Standard Deviation 7.05 |
| Abatacept | Synovitis, Tenosynovitis and Erosions Scores (GSUS and PDUS) | 16 week GSUS | 12.75 score on scale | Standard Deviation 2.22 |
| Abatacept | Synovitis, Tenosynovitis and Erosions Scores (GSUS and PDUS) | baseline PDUS | 5.25 score on scale | Standard Deviation 5.12 |
| Abatacept | Synovitis, Tenosynovitis and Erosions Scores (GSUS and PDUS) | 16 week PDUS | 2.00 score on scale | Standard Deviation 1.83 |
| Placebo | Synovitis, Tenosynovitis and Erosions Scores (GSUS and PDUS) | 16 week PDUS | 2.25 score on scale | Standard Deviation 1.89 |
| Placebo | Synovitis, Tenosynovitis and Erosions Scores (GSUS and PDUS) | baseline GSUS | 16.00 score on scale | Standard Deviation 4.83 |
| Placebo | Synovitis, Tenosynovitis and Erosions Scores (GSUS and PDUS) | baseline PDUS | 1.50 score on scale | Standard Deviation 1 |
| Placebo | Synovitis, Tenosynovitis and Erosions Scores (GSUS and PDUS) | 16 week GSUS | 17.75 score on scale | Standard Deviation 5.19 |